The regulation of platelet adhesion to sites of vascular injury involves a well-orchestrated interaction of several proteins and plays an important role in both hemostasis and thrombosis. One such protein that contributes to platelet adhesion is von Willebrand Factor (vWF), a large multimeric glycoprotein present in blood plasma. VWF is hypothesized to interact with platelet receptor GPlb-α through its A1 domain thereby promoting platelet rolling and adhesion (Moake et al. (1986) J. Clin. Invest. 78:1456-61). Subsequent to platelet rolling and adhesion, a platelet/fibrin plug may form which results in the cessation of bleeding. However, an excessive platelet and/or coagulation response may lead to pathological thrombotic conditions.
Given that current therapies directed towards inhibiting platelet activation (e.g., GPllbllla, ADP receptor, cyclo-oxygenase or phosphodiesterase antagonists) or coagulation (e.g., thrombin and factor Xa inhibitors) are associated with bleeding complications, there exists a need to develop agents that are able to substantially inhibit thrombosis without significantly impairing hemostasis.